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The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling

(2017) BLOOD. 129(4). p.460-472
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Abstract
Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.
Keywords
EPITHELIAL-MESENCHYMAL TRANSITION, SMAD-INTERACTING PROTEIN-1, STEM-CELL, HOMEOSTASIS, MIR-200 FAMILY, LYMPHOBLASTIC-LEUKEMIA, POSTMITOTIC, NEURONS, REPRESSORS ZEB1, SELF-RENEWAL, TGF-BETA, IN-VITRO

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Chicago
Li, Jin, Tamara Riedt, Steven Goossens, Carmen Carrillo Garcia, Sabrina Szczepanski, Maria Brandes, Tim Pieters, et al. 2017. “The EMT Transcription Factor Zeb2 Controls Adult Murine Hematopoietic Differentiation by Regulating Cytokine Signaling.” Blood 129 (4): 460–472.
APA
Li, Jin, Riedt, T., Goossens, S., Garcia, C. C., Szczepanski, S., Brandes, M., Pieters, T., et al. (2017). The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling. BLOOD, 129(4), 460–472.
Vancouver
1.
Li J, Riedt T, Goossens S, Garcia CC, Szczepanski S, Brandes M, et al. The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling. BLOOD. 2017;129(4):460–72.
MLA
Li, Jin, Tamara Riedt, Steven Goossens, et al. “The EMT Transcription Factor Zeb2 Controls Adult Murine Hematopoietic Differentiation by Regulating Cytokine Signaling.” BLOOD 129.4 (2017): 460–472. Print.
@article{8517350,
  abstract     = {Epithelial-to-mesenchymal-transition (EMT) is critical for normal embryogenesis and effective postnatal wound healing, but is also associated with cancer metastasis. SNAIL, ZEB, and TWIST families of transcription factors are key modulators of the EMT process, but their precise roles in adult hematopoietic development and homeostasis remain unclear. Here we report that genetic inactivation of Zeb2 results in increased frequency of stem and progenitor subpopulations within the bone marrow (BM) and spleen and that these changes accompany differentiation defects in multiple hematopoietic cell lineages. We found no evidence that Zeb2 is critical for hematopoietic stem cell self-renewal capacity. However, knocking out Zeb2 in the BM promoted a phenotype with several features that resemble human myeloproliferative disorders, such as BM fibrosis, splenomegaly, and extramedullary hematopoiesis. Global gene expression and intracellular signal transduction analysis revealed perturbations in specific cytokine and cytokine receptor-related signaling pathways following Zeb2 loss, especially the JAK-STAT and extracellular signal-regulated kinase pathways. Moreover, we detected some previously unknown mutations within the human Zeb2 gene (ZFX1B locus) from patients with myeloid disease. Collectively, our results demonstrate that Zeb2 controls adult hematopoietic differentiation and lineage fidelity through widespread modulation of dominant signaling pathways that may contribute to blood disorders.},
  author       = {Li, Jin and Riedt, Tamara and Goossens, Steven and Garcia, Carmen Carrillo and Szczepanski, Sabrina and Brandes, Maria and Pieters, Tim and Dobrosch, Linne and Guetgemann, Ines and Farla, Natalie and Radaelli, Enrico and Hulpiau, Paco and Mallela, Nikhil and Froehlich, Holger and La Starza, Roberta and Matteucci, Caterina and Chen, Tong and Brossart, Peter and Mecucci, Cristina and Huylebroeck, Danny and Haigh, Jody J and Janzen, Viktor},
  issn         = {0006-4971},
  journal      = {BLOOD},
  keyword      = {EPITHELIAL-MESENCHYMAL TRANSITION,SMAD-INTERACTING PROTEIN-1,STEM-CELL,HOMEOSTASIS,MIR-200 FAMILY,LYMPHOBLASTIC-LEUKEMIA,POSTMITOTIC,NEURONS,REPRESSORS ZEB1,SELF-RENEWAL,TGF-BETA,IN-VITRO},
  language     = {eng},
  number       = {4},
  pages        = {460--472},
  title        = {The EMT transcription factor Zeb2 controls adult murine hematopoietic differentiation by regulating cytokine signaling},
  url          = {http://dx.doi.org/10.1182/blood-2016-05-714659},
  volume       = {129},
  year         = {2017},
}

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